TBG Levels Research Articles

Maternal thyroid function in pregnancy

In healthy pregnant women, the regulation of thyroid function depends upon several factors. Three factors act independently to increase thyroid hormone requirements: 1) the marked increase in the binding capacity of serum due to high TBG levels; 2) the direct stimulation of the thyroid by human chorionic gonadotropin, acting as a thyrotropic hormone; and 3) the increase in placental deiodinating activity, which may contribute to modify thyroid hormone metabolism. These stimulatory events result in a physiological adaptation of the maternal thyroid gland to pregnancy, as long as the availability of iodine for the thyroidal "machinery" remains sufficient. Our studies were performed in an area where the iodine intake is precisely at the lower limit of the needs for healthy non pregnant adult subjects (less than 100 micrograms/day). In these conditions, decreased iodine availability during gestation leads to relative iodine deficiency and hence, pregnancy constitutes a "challenge" for the thyroid gland. It was shown that excessive thyroidal stimulation occurred in as much as one third of pregnancies in Brussels, accompanied by relative hypothyroxinemia, marked elevation in serum TG levels and goitrogenesis. About 10% of women had developed a goiter at parturition, which was only partially reversible during the postpartum period. A randomized prospective trial was then undertaken in euthyroid pregnant women who were below 16 weeks of gestation at initial presentation and who fulfilled biochemical criteria of excessive thyroidal stimulation (high molar T3/T4 ratio, low normal free T4 index, elevated serum TG). Thyroid function and volume were monitored sequentially during gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

The "feto-maternal" thyroid function interrelationships in an iodine-deficient region in Africa—the role of T3 in possible fetal defence

The thyroid status was investigated in 26 pregnant African women at term delivery in an iodine-deficient region (Jengere) of Nigeria, West Africa including the measurement of serum T4, T3, TSH, thyroxine binding capacity, TBG, free thyroxine index (FT4I) and the results were matched with those obtained in a corresponding group of 46 women at delivery in Jos, the non-iodine-deficient region which was used as a control. Corresponding cord-blood samples were obtained from all the neonates of the two groups. Twenty-three urinary samples in the former and 14 in the latter group were analysed for iodide levels to ascertain the degree of iodine deficiency. The results demonstrate that compared to the values seen in the Jos group the maternal serum T4, T3 and FT4I levels were significantly reduced in the iodine-deficient group, while TSH, TBG and thyroxine binding capacity were elevated. Cord serum samples showed a corresponding fall in T4 and FT4I levels in the group from the iodine-deficient region, while the T3 levels were significantly elevated with a concurrent significant rise in TSH and TBG levels. Significant correlations were found between the maternal and cord serum T4, TSH, TBG, thyroxine binding capacity and FT4I levels, but not T3. From these findings we suggest that fetal T3 plays an important defensive role against the danger of long-standing environmental iodine deficiency.

Studies on Thyroid Hormone Autoantibody in Two Euthyroid Cases with Spuriously High Value of Serum Free Triiodothyronine

Spuriously high value of serum free triiodothyronine (FT3: Amerlex free T3 kit, Amersham, UK.) was noted accidentally on routine laboratory examination of two clinically euthyroid patients (case 1: FT3; 18.5 pg/ml, FT4; 1.1 ng/dl, T3; 103 ng/dl, T4; 8.2 micrograms/dl, TSH; 1.74 microU/ml, case 2: FT3; 8.5 pg/ml, FT4; 1.1 ng/dl, T3; 137 ng/dl, T4; 8.9 micrograms/dl, TSH; 1.45 microU/ml), the former with poorly controlled diabetes (FBG 253 mg/dl, HbA1c 12.1%) and the latter with essential hypertension (184/108 mmHg). Although the hypertensive patient showed mild diffuse goiter, there was no evidence that the patients had autoimmune thyroid diseases because anti-thyroglobulin antibody tests measured by radioimmunoassay and MCHA, TGHA or TBII were all negative. Their serum levels of TBG were within the normal range. Further studies revealed that both patients' sera had unusual binding activity to labelled polyaminocarboxy T3 (125I-aT3) but not labelled T3 (125I-T3). Furthermore, this binding protein was precipitated by goat anti-human immunoglobulin G (IgG). The IgG purified from both patients' sera also showed strong binding activity to 125I-aT3, which was inhibited by unlabelled T3 in a dose dependent manner. In conclusion, we found anti-T3 antibody in two clinically euthyroid patients with no apparent evidence of complicating autoimmune thyroid diseases. The stronger binding activity to polyaminocarboxy T3 rather than T3 may lead to the spuriously high value of serum FT3. The mechanisms of the production of such autoantibodies in our cases should be further investigated.

Effect of growth hormone therapy on thyroid status of girls with Turner's syndrome*

The effect of recombinant human growth hormone (rhGH) administration on thyroid function was studied in 14 girls with Turner's syndrome for 18 months. All patients were euthyroid and had no documented GH deficiency. Treatment with rhGH, administered as daily subcutaneous injections in a dose of 0.15 IU/kg/day, led to a decrease of serum T4 levels from 124 +/- 4 (mean +/- SEM) to 106 +/- 4 nmol/l (P less than 0.05) after 6 months of therapy. Thereafter serum T4 levels returned progressively to baseline levels. Serum TBG levels increased consistently from 21.9 +/- 0.5 to 24.4 +/- 0.9 mg/l (P less than 0.05) after 3 months. Serum T3 and TSH levels did not change significantly during rhGH administration. The T3/T4 ratio (x 100) increased from 1.9 +/- 0.1 to 2.2 +/- 0.1 (P less than 0.05) after 6 months of treatment and returned thereafter to baseline levels. The observed changes in T3/T4 ratio demonstrated a striking parallelism with the changes in height velocity and plasma IGF-I levels. We conclude that rhGH treatment results in a transient alteration of the thyroid status in girls with Turner's syndrome. The functional importance of this phenomenon, in particular its role in the concomitant growth acceleration, remains to be established.

The Incidence of Clinical Thyroid Dysfunction in an Unselected Group of Pregnant and Post Partum Women

This study has examined the incidence of thyroid dysfunction during pregnancy and up to six months post partum in 65 women attending an antenatal clinic in the West of Scotland. Five were found to be positive for thyroid antibodies at presentation and in these the antibody titre fluctuated during pregnancy and in the post partum period. One patient developed thyroglobulin antibodies post partum. Mean total T3 and total T4 levels rose during pregnancy but had normalised by six weeks post partum. The changes in FT4 and TBG levels observed during pregnancy did not normalise until after six weeks post partum. Only one patient developed any biochemical evidence of thyrotoxicosis post partum and this was not found to be associated with the presence of thyroid antibodies. No patient showed any evidence of hypothyroidism.

A Case of Pseudo-Bartter's Syndrome Associated with Hypergastrinemia, Thrombocytosis and Increased Serum Thyroxine-Binding Globulin.

A housewife, 40 years of age, was admitted with dysesthesia of the extremities, muscle weakness, and attacks of adynamia and thirst. She had been taking a laxative for more than 20 years. On physical examination, blood pressure was 94/56 mmHg. Laboratory tests revealed thrombocytosis, low serum K and marked increases in both plasma renin activity and serum aldosterone. Serum TBG was increased. Serum gastrin was also markedly increased and could not be enhanced by exogenous secretin. Both angiotensin 11 loading test and noradrenalin loading test failed to increase blood pressure. Ammonium chloride loading to examine the disturbance of urinary acidification was abnormal in the short term test and borderline in the long term test. Following a diagnosis of pseudo-Bartter's syndrome induced by long term intake of laxative and repeated diarrhea, the administration of laxative was interrupted and potassium, indomethacin and spironolactone were administered. However, serum K remained low. Hypergastrinemia, thrombocytosis and a high serum TBG level also persisted, the causes of which remain unknown. This is the first reported case of pseudo-Bartter's syndrome associated with hypergastrinemia, thrombocytosis and increased serum TBG.

MATURATION OF THYROID FUNCTION IN NORMAL HUMAN FOETUSES

The functional maturation of an independent foetal thyroid activity was investigated in the present study. Serum concentrations of total T4, free T4, TSH and TBG were measured in 23 foetuses between 18 and 31 weeks' gestational age. Foetal samples were collected by transabdominal needling from the placental cord insertion. TT4, FT4, TBG and TSH levels significantly increased with gestational age. FT4 levels were comparable with the adult range by 28 weeks' gestation; TBG levels reached adult values at approximately 30 weeks, while TT4 was lower than adult levels throughout the whole period studied. TSH values were, in all cases, higher than the normal adult range. A significant positive correlation was present between TT4 and TBG, TT4 and TSH, and TBG and TSH levels; on the contrary, no correlation was demonstrated between FT4 and TSH levels. The TSH/TT4 ratio significantly decreased with gestational age. The results suggest an incomplete responsiveness of the foetal thyroid gland to TSH, while the feedback control system between pituitary and thyroid is operating at a different set point from that in post-natal life. The normal range of thyroid parameters established is of clinical relevance for the antenatal diagnosis, and eventual treatment of thyroid disorders that may seriously damage foetal development and maturation.

A study of thyroid function in cancer cachexia.

The mechanisms responsible for cancer cachexia have not yet been clarified. To further investigate the role played by the hypothalamic-pituitary-thyroid axis in cancer cachexia, we evaluated serum levels of T3, FT3, T4, FT4, TSH and TBG in a group of 26 cancer patients, 14 of whom showed cachexia, whereas the other 12 had a body weight within the normal range despite their advanced diseases. As controls, 58 healthy subjects and 11 patients with benign weight loss were included in the study. Low levels of both T3 and FT3 were observed in all patients with benign weight loss and in 9/12 advanced cancer patients who had no cancer cachexia. On the contrary, only 4/14 cachectic cancer patients presented decreased values of T3 and FT3. Moreover, the mean serum levels of T3 and FT3 in cachectic oncologic patients were significantly higher than those seen both in non-cachectic cancer patients and in patients with benign weight loss. Since T3 is the biologically active thyroid hormone, the lack of a decrease in its production might play a role in the pathogenesis of cancer cachexia.

Thyroid function tests in acute viral hepatitis: relative reduction in serum thyroxine levels due to T4-TBG binding inhibitors in patients with severe liver cell necrosis

Thyroid function tests were evaluated in 34 patients with acute viral hepatitis (AVH) and in 38 healthy controls (C). As expected, AVH patients displayed a significant increase in T4, rT3 and TBG serum levels with respect to C, while FT4 and TSH concentrations were similar. A positive correlation between TBG and T4 was evident in C, but not in AVH. In this group there was, instead, an inverse correlation between the sum of serum levels of GOT + GPT and T4 concentrations. When AVH patients were divided in "high necrosis" (HN, serum GOT + GPT greater than 2000 UI/l) and "low necrosis" (LN, serum GOT + GPT less than 2000 UI/ml) groups, we found a significant reduction in both T4 and T3 serum concentrations in HN with respect to LN, despite similar levels of TBG, albumin, FT4 and TSH. The hypothesis that thyroid-hormone binding inhibitors (THBI), released during severe liver cell injury, accounted for an impaired serum binding capacity in HN-AVH, was confirmed by the significant increase in FT4/T4 ratio and by the demonstration of THBI activity in pooled sera of these patients, with respect to LN subgroup. Our present finding may clarify the unexplained observation of reduced T4 levels in patients with fulminant hepatitis and the ominous prognostic significance of a "low T4 syndrome" in subjects with severe liver disease and/or other systemic illnesses.

Euthyroid Hyperthyroxinemia Due to Familial Excess of Thyroxine-Binding Globulin

The correct diagnosis of benign hyperthyroxinemia in this patient and his family members will spare them the unnecessary testing and treatment for thyrotoxicosis that has befallen some such patients. Results of the usual blood tests for assessment of thyroid function, such as T4, T3, and thyrotropin determinations, were not uniformly diagnostic, and were potentially misleading. An increased T4 level, a nonsuppressed TSH level, normal levels of FT4 and FT4D, and a low level of T3RU were clues that led to a request for specific measurement of serum TBG levels in multiple family members; family testing was essential for the diagnosis of euthyroid hyperthyroxinemia due to familial hepatic overproduction of TBG.

Studies on the pituitary and thyroid function in patients with nonthyroid illnesses

Serum thyroid hormone and TSH concentrations were determined in patients with nonthyroidal illnesses (NTI) including 26 patients with chronic renal failure on hemodialysis, 15 patients with end-stage malignancy and 21 normal controls. Serum TSH levels were measured by a highly sensitive immunoradiometric assay Kit (RIA-gnost hTSH) and free-T4 levels were determined not only by both back-titration method and T4 derivative method, but also by magnesium precipitation method using equilibrium dialysis. TSH levels in normal controls ranged from 0.6 to 2.4 microU/ml. In 40 of 41 patients with NTI, serum T3 levels were less than 100 ng/dl, and 37 patients had diminished T3 levels, as compared with those in normal controls. Moreover, serum T4 levels were also diminished in 19 patients with NTI, and T4 levels related significantly to serum TBG levels in all patients with NTI (r = +0.76, p less than 0.01), suggesting that the diminution of T4 levels in patients with NTI can be explained partly by decreased TBG levels. However, it was remarkable that free T4 levels in serum, determined by RIA kits, were decreased in approximately half of the patients with NTI. Free T4 levels by the magnesium precipitation method were still lower in these patients when compared with those in normal controls. Serum TSH levels in patients with NTI showed a wide scattering from below to above the normal range, and the mean value was not significantly different from that in normal controls. No significant relations were found between TSH levels and T4, T3, or free T4 levels in patients with NTI.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid function in prematures with respiratory distress syndrome (RDS).

Reports on thyroid function in newborns with respiratory distress syndrome (RDS) are controversial, the significance of obtained results is not clear. Therefore we conducted a longitudinal study of thyroid function in 35 infants with RDS (gestational age 24-36 weeks, birth weights 650-2770 g). 43 well prematures, matched for gestational age, served as controls. No significant differences were observed in cord blood TSH, T3, T4, TBG values and T4:TBG ratios between infants with and without RDS. Prematures with RDS showed lower levels of T3, T4, TBG and T4:TBG at 24 hours of age and increases of TSH values at 72 hours. Subsequently these prematures exhibited a spontaneous rise in thyroid hormone levels. Even non-surviving RDS-infants had initial T3, T4, T4:TBG and TSH values within the normal range. Thyroid hormone concentrations correlated significantly with the severity of pulmonary disease. Depressed thyroid hormone levels were found to be the result and not the cause of RDS. T4 or T3 therapy is not warranted in this condition.

HYPOPHYSEAL-THYROID AXIS FUNCTION IN EPILEPTIC CHILDREN ON ANTICONVULSANT MONOTHERAPIES

Antiepileptic drugs have been inconstantly reported to involve thyroid hormone synthesis and/or metabolism. We have performed a TRH test in 25 children of both sexes, aged 5-13 1/2 years, clinically euthyroid, on unchanged monotherapy from the start (at least 2 years). Serum basal levels of TSH, T4, T3, TBG and serum TSH levels after TRH were assayed by commercial RIA kits. Statistical analyses included mean, SD, Student's t test. Valproate-treated children (VPA-C) (10 subjects) showed TSH levels both before (p<0.05) and after TRH (p<0.01 or 0.001) higher than normal children (NC). Serum T4 levels in VPA-C, carbamazepine-treated children (CBZ-C) (7 subjects) (p<0.001) and phenobarbital-treated children (PB-C) (8 subjects) were lower than in NC (p<0.01). PB-C had higher T4 levels than CBZ-C (p<0.01). Our data show a subclinical primary hypothyroidism in VPA-C. Low T4 with normal TBG and normal levels of TSH both before and after TRH in CBZ-C and PB-C could be explained by a decreased thyroidal synthesis and/or an enhanced peripheral metabolism with a concomitant depressive influence on hypothalamic-pituitary axis or a T3-depending cellular euthyroidism. * Partially supported by a grant of Italian Ministry of Education

Circulating thyroid hormones in primates with mild or severe hepatitis following liver transplantation.

In order to study the effects of acute immunologically mediated liver disease on circulating thyroid hormones, serum levels of thyroxine (T4, total and free) and triiodothyronine (T3) were measured in 8 baboons before and for 60 days after allogeneic liver transplantation. In 3 animals early rejection and jaundice developed; T4 levels declined as liver function deteriorated. In the 5 tolerant animals liver function was only temporarily deranged without jaundice and there was a consistent early rise in T4 (P less than 0.01) followed by a later fall. T3 concentrations were relatively normal in both groups. The T3 resin uptake test remained virtually unchanged in all animals. Serum T4 and T3 responses to exogenously administered bovine thyrotropin (TSH) were similar in the jaundiced and anicteric animals. We conclude that the early rise in T4 in the tolerant animals was caused by transient increases in thyroid binding globulin in (TBG) while the fall in thyroid hormones in these and in the jaundiced animals was related to a decline in TBG levels. Thyroid responsiveness to TSH is not disturbed by moderately deranged liver function.

Measurement of thyroxine uptake from serum by cultured human hepatocytes as an index of thyroid status: reduced thyroxine uptake from serum of patients with nonthyroidal illness.

The uptake of T4 from human serum by cultured human hepatoma cells, Hep G2, was compared with the free T4 estimates by equilibrium dialysis (DT4) and a resin uptake method (FT4I). The cellular uptake of T4 (CT4) was highly correlated with DT4 values (r = 0.97; P less than 0.0005) and FT4I values (r = 0.99; P less than 0.0005) in sera from euthyroid subjects and hypothyroid and thyrotoxic patients. In patients with abnormal levels of serum T4-binding globulin, the fractional uptake of T4 decreased as the TBG level increased, and the CT4 value remained within the normal range. Addition of increasing amounts of T4 to serum from a hypothyroid patient did not alter the relationships between CT4 and FT4I and between CT4 and DT4. DT4 and CT4 measurements were compared in sera from 13 patients with severe nonthyroidal illness (NTI). Six samples had DT4 values that clearly overestimated the cellular uptake, 2 patients had DT4 values in the thyrotoxic range but normal CT4 values, and 2 patients had DT4 values in the midnormal range and CT4 values below normal. When FT4I and CT4 values were compared in 19 NTI patients, 5 had FT4I values below the normal range and normal CT4 values. Overall, among patients with NTI, FT4I was low in 11 (58%), normal in 8 (42%), and high in 0; CT4 was low in 6 (32%), normal in 13 (68%), and high in 0, and DT4 was low in 2 (15%), normal in 9 (69%), and high in 2 (15%). In patients with NTI, the results of in vitro estimations of free T4 do not always correlate with the transfer of T4 to tissues, as assessed by T4 uptake in human hepatoma cells. In patients with NTI, equilibrium dialysis may overestimate and resin uptake measurements may underestimate the amount of T4 taken up by tissues. In some patients with severe NTI, tissue uptake of T4 is reduced.

427 SHORT STATURE ASSOCIATED WITH TBG EXCESS: IMPROVEMENT WITH T3 TREATMENT

Euthyroid hyperthyroxinemia has been described in association with TBG excess. We report a 6 1/2 yr old male with high TBG levels (17 mg/dl) and high T4 of 24.5 ug/dl, who also has short stature (-3 SD), delayed bone age (BA) of 2 1/2 yr and hyper TSH response to TRH testing (max value 52.2 μIU/ml). Other data: vital signs normal, wt at 5 percentile, T3=405 μg/dl, FT4= 4.6 ng/dl, FT3=768 pg/dl. Thyroid uptake was 23.7%, TS RU 21.8% (nl 37.5-47.5%), basal TSH=5.1 μIU/ml. Left Ventricular Ejection Time (LVET) was 0.24 sec (nl). WISC-R I.Q. was nl, sleeping pulse rate was nl. T3 supplement was started and gradually increased to 30 μg/day. The patient was followed at weekly intervals. No clinical signs of hyperthyroidism occurred. Serum T4 decreased from 19 to 6.1 μg/dl, T3 increased to 640 ng/dl, TRH-TSH test was suppressed (max level 1.8). LVET remained normal at 0.24 sec. Growth velocity (6V) increased from 5 cm/yr to annualized GV of 9 cm/yr after 3 mo of treatment. Both parents of this child had nl thyroid tests. A 4 1/2 yr male sibling is affected also. His TBG=20.6 mg/dl, basal TSH=4 μIU/ml, T4=31 μg/dl, ht is on the 10 percentile (was in the 50 percentile in the 1st 2 years of life), BA =3 yr. In summary: 1)these children have TBG excess consistent with X-linked recessive inheritance 2)the abnormal TRH stimulation test, delayed BA, and short stature, improved growth after T3 supplementation suggest inadequate compensatory mechanisms despite the hyperthyroxinemia 3)there can be variability in expression of mild thyroid insufficiency in conditions of excess TBG.

Thyroregulatory changes associated with smoking in 70-year-old men.

In a previous study we have analysed serum free T4 concentrations in a representative population of 70-year-old men. In the present study the effect of previous or present tobacco smoking on free T4, T4, T3, rT3, TSH and thyroid hormone binding proteins was analysed in 181 of the 460 men, excluding those with past or present goitre, those who were obviously ill or had died between 70 and 75 years of age and those who had any disease or medication influencing free T4 concentrations. Smokers had higher T4 and rT3 levels, and lower TSH levels but T3 levels no different from non-smokers. The difference in T4 levels, but not rT3 or TSH levels, between smokers and non-smokers could be attributed to differences in body mass and also to differences in TBG levels. The results indicate that tobacco smoking is associated with long-term alterations in thyroregulatory function.

Endocrine involvement in children with beta-thalassaemia major. Transverse and longitudinal studies. I. Pituitary-thyroidal axis function and its correlation with serum ferritin levels.

Thyroid function was investigated by a TRH test in 24 clinically prepubertal children, 3-15 years old with beta-thalassaemia major; in 7 of them the test was repeated once and in 2 twice at intervals of at least 12 months. Basal T4, T3, TBG and TSH levels and the TSH levels during a TRH test were determined and correlated with age and serum ferritin levels. Basal serum T4, T3 and TBG levels were lower and serum TSH levels were higher during the test and in the basal state in thalassaemia major children than in control children. These results show a compensated sub-clinical primary hypothyroidism. The transversal study did not show any significant correlation between the hormonal parameters studied and chronological age or serum ferritin levels. In contrast, the longitudinal study showed a significant correlation between pituitary-thyroidal axis function and siderosis (positive correlations between the variations of TSH levels as delta, peak, 30 and 45 min values and the variations of serum ferritin levels). The thyroid impairment seems not to be correlated with serum ferritin levels in the transversal study because of the presence of an individual different sensitivity of the gland to the iron overload. The ferritin dependence of this impairment is shown only by longitudinal studies where individual differences in sensitivity of the gland are absent.(ABSTRACT TRUNCATED AT 250 WORDS)

La fonction thyroïdienne dans le syndrome néphrotique

Serum Total Thyroxine (T4), Triiodothyronine (T3), Free Thyroxine (FT4), Free Triiodothyronine (FT3) Reverse Triiodothyronine and T3 Resin Uptake (T3RU) as well as basal and post stimulating TSH were measured in twenty clinically euthyroid patients with the nephrotic syndrome. In comparison with control values, our patients showed (1) significantly lowered mean serum TBG levels (p less than 0,05) (2) unmodified mean serum T3, FT3 and rT3 values (3) significantly lowered mean serum T4 and FT4 levels (p less than 0,001 and p = 0,027 respectively) (4) significantly higher mean basal TSH, and increased TSH response to TRH. We found a significant correlation between proteinemia and T4 or FT4 (p less than 0,001; p less than 0,01 respectively). In summary, our study: Shows that the low Total T4 observed in the Nephrotic Syndrome is not only due to a decreased protein bound T4, but also to a decreased FT4; And brings evidence for mild hypothyroidism in nephrotic patients.

THYROID HORMONES IN NON‐INSULIN‐DEPENDENT DIABETES BEFORE AND AFTER DIETARY TREATMENT

In a group of 8 moderately obese non-insulin-dependent diabetics, both serum total T3 and T4 concentrations and serum free T3 and T4 concentrations were significantly lower than control values. Serum TBG levels did not differ. Five patients demonstrated an apparently successful response to dietary treatment with loss of symptoms and glycosuria and fall in post-prandial blood glucose and HbA1. Serum concentrations of thyroid hormones and TBG, however, were not significantly altered. These abnormalities may be unrelated to hyperglycaemia and may reflect the nutritional status of the patients.